1. Field of the Invention
The present invention pertains to a method and novel compositions containing gentian from the gentianaceae family of plants for the treatment of vaginal yeast infections and other fungal infections caused by various fungal and yeast forms such as Candida and Cryptoccus. More particularly, the invention pertains to novel compositions and preparations obtained from the root or seeds of the plant having the pharmaceutical name of Radix gentianae Longdancao for the treatment of vaginal yeast infections and other fungus and yeast infections caused by Candida albicans and Cryptoccus.
The plant Radix gentianae Longdancao is also known by the botanical names Gentiana scabra Bge, Gentiana triflora Pall, Gentiana manshurica Kitag, Gentiana algida Pall, Gentiana regescens Fransh and Gentiana lutea which will be referred to collectively as Radix gentianae Longdancao. Radix gentianae Longdancao may be used to prepare novel antifungal preparations and novel medicaments in the form of topical creams, liquids, lotions, capsules, lozenges and suppositories. The novel preparations from Radix gentianae Longdancao may be applied topically or transmucosally to treat cutaneous and mucosal syndromes caused by candida infection or taken internally in the form of lotions, liquids, tablets and capsules for the treatment of systemic Candida and Cryptoccus infections.
The novel method of treatment of Candida and Cryptoccus infection with novel preparations from Radix gentianae Longdancao is effective in treating not only cutaneous and mucosal candidiasis but also systemic candidiasis involving the bloodstream and metastatic invasion of the meninges, bones, joints, peritonium and myocardium. The novel Radix gentianae Longdancao preparations, when taken internally, pass through the digestive system and enter the blood stream for the treatment of systemic Candida infections and pass the blood brain barrier to treat meningeal candidiasis and Cryptoccus meningitis in AIDS patients. The novel preparations of the invention do not require injection or IV application for the treatment of fungal infections of Candida albicans, Candida tropicalis and other Candida species referred to collectively as Candida and Cryptoccus neoformans and other Cryptoccus species collectively referred to as Cryptoccus. The novel Radix gentianae Longdancao preparations are advantageous over the prior art since they are nontoxic to the patient and may be utilized in patients having weak or compromised immune systems such as in the case of AIDS patients, leukemia, Hodgkin's disease, neutropenia, hematologic diseases and endocrinopathies.
The method and novel preparations of the invention may also be utilized to treat the mucus membrane infections such as vaginal yeast infections, oral candidiasis and urinary tract candidiasis in both patients with normal immune systems and immuno-compromised patients through the use of suppositories and solutions prepared from the Radix gentianae Longdancao. The novel preparations may be applied in the form of suppositories, liquids, creams and other formulations for use in the treatment of mucosal infestations of Candida albicans such as in the case of vaginal yeast infections, oral thrush or oropharyngeal moniliasis and for systemic infections caused by Candida and Cryptoccus by the utilization of capsules, lotions and liquids prepared in accordance with the present invention.
2. Description of Related Prior Art
A number of species of the fungus Candida albicans are capable of causing candidiasis. Candida albicans can switch reversibly and at high frequency among at least seven different phenotypes defined by colony morphology. The changes in Candida albicans are often associated with changes in virulence which are related to the particular balance of the flora composition in the particular organ as well as immunological condition of the patient. Candida and Cryptoccus are ubiquitous in the environment and generally do not create problems, except where the immune system is weak or compromised or the normal floral balance of the skin, mucous membranes, gastrointestinal tract or body is changed as a result of a variety of factors such as stress, changes in pH, nutrition and changes in the immune system of the patient. Candida albicans is part of the normal flora of the skin, mucous membranes in the mouth, throat, intestine and genital tract. Normally Candida fungus lives in a healthy balance with the other bacteria and yeasts in the body as part of the normal flora. As a result infection is always present and Candida albicans is the most common systemic mycosis.
A number of environmental stimuli are known to trigger or to block the growth of candidiasis. Candida flora is generally kept in balance by killer toxins produced by other yeast and fungus in the normal flora of the body. Abnormal physiological changes in the epithelium may be involved together with a host of other factors, including genetics, nutrition, stress and other factors that result in infections of various organs of the body, particularly in immunosuppressed individuals or in individuals that have had the normal floral balance changed by the taking of wide spectrum antibiotics such as tetracycline. The taking of such wide spectrum antibiotics has in many cases eliminated beneficial flora which keep Candida albicans in check and prevented candidiasis.
In addition to a great number of environmental factors a host of immunological conditions of the patient result in varying degrees of susceptibility to candidiasis and Cryptoccus infections. Cancer patients, organ transplant patients and patients with immunologic disorders, chronic infections, leukemia, acquired immunodeficiency disorder diseases (AIDS), Hodgkin's disease, neutropenia and other hematologic diseases and endocrinopathies including diabetes leave the patient particularly susceptible to fungal infections by Candida albicans and Cryptoccus. Such immunologically compromised patients are at a risk of systemic candidiasis, Cryptococcal meningitis and other infections resulting from the inability of their immune system to destroy ubiquitous fungus of Candida albicans and Cryptoccus which are part of the normal environment.
It is known that Candida albicans and Cryptoccus neoformans are killed by neutrophils in the normally healthy patient. Where the neutrophils have impaired killing capacity or the patient is neutropenic such as those having leukemia or impaired immunological systems such patients are particularly susceptible to Candida albicans and Cryptoccus neoformans. As a result intact cell mediated immunity is critical to prevent infection against Candida albicans and Cryptoccus neoformans. In the case of immunologically suppressed patients opportune Candida albicans and Cryptococcal infections are particularly difficult to treat. Treatment of AIDS patients with cryptococcal infection are particularly difficult to treat, particularly where Cryptococcal meningitis is involved due to problems in the administration of drugs, particularly amphotericin B which is toxic and which must be administered by IV.
In the case of patients with normal immune systems fungal infections of the mouth produce painful oropharyngeal moniliasis or thrush if wide range antibiotics such as tetracycline have destroyed a normal floral balance which blocks the growth of Candida albicans. In this regard it is to be noted that there is a confusion of nomenclature and various names have been applied to Candida organisms such as Monilia albicans, Saccharomyces albicans, Odium albicans but usually the Candida albicans is the most commonly used and will be referred to herein as Candida or Candida albicans. Candida albicans grows readily in a moist environment at a pH of more than 5. Lactobacillus normally maintains the pH at a range of 4.5 to 5 and as a result lactobacillus provides a natural floral balance to candidiasis.
Fungal infections of the vagina or urinary tract are difficult to eradicate and frequently recur but are rarely life-threatening. The normal pH of the genital tract is 4.5 to 5 which is maintained by lactobacillus. The absence of lactobacillus and a normal pH promotes candidiasis as well as the herpes virus, birth control pills, a weak immune system, genetic factors, stress and a host of other factors which foster the growth of yeast and fungal infections of the genital tract.
The treatment of fungus and yeast infections has a long history which originated from herbs, plants and compositions isolated from vegetation. In fact, amphotericin B was isolated from rotting vegetation on the banks of the Oronico River in Venezuela. Amphotericin B, despite its toxicity and the fact that it was discovered back in 1956, still remains the most effective wide spectrum fungicide in use today. Amphotericin B is a polyene and remains the most efficacious and drug of choice for many deep seated fungal infections caused by Candida and Cryptoccus. Amphotericin B however is toxic and has exhibited a number of adverse side effects. Other polyenes in use include nystatin, candicidin, primaricin and mepatricin. The toxicity and adverse side effects of the polyene drugs have in many cases limited their applicability to external and topical applications. See Scientific American Medicine (1980), Vol. 2, p. 11-16, 7-8; Topley and Wilson's Principles of Bacteriology, Virology And Immunity, 8th ed. (1990), Vol. 1, p. 144-149; Lederberg (ed.) Encyclopedia of Microbiology, (1992) Vol. 1, p. 135; Zinsser Microbiology, 20th ed. (1992), p. 337-338, 682-686; 1089, 1136-1139, 1142-1143; Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th ed. (1996), p. 207-208; and Principles of Pharmacology, Paul L. Munson (1995) p. 1401-1411.
In addition to polyene compounds various azole derivatives including ketoconazole, fluconazole and itraconazole are used for systemic infections. Other azole derivatives include miconazole, clotrimazole, terconazole and econazole. These azole derivatives possess a broad spectrum of antifungal activity, have low toxicity and consequently the azole compounds are in wide use and are administered orally and systemically for systemic infection and are administered topically for dermatophytosis, vaginal mycoses and for skin and mucocutaneous infections. Ketoconazole, fluconazole and itraconazole are typically used for systemic fungal infections and are administered orally.
In addition to the polyene and azole compounds 5-fluorocytosine is commonly used in combination with amphotericin B for systemic infections caused by Cryptoccus neoformans and Candida, particularly in immuno-compromised patients. In addition other treatments and older treatments for mucosal candidiasis and smooth skin infections with Candida albicans have been used such as Whitfields Ointment which is a mixture of 6% benzoic acid and 3% salicylic acid and gentian violet. Principles of Pharmacology, Paul L. Munson, (1995), p. 1410 and The Merck Index, 10th Ed. (1981), p. 627. Gentian violet is a chemical compound that is not present in gentian plants or gentian root.
A wide variety of pharmaceutical preparations are available for the treatment of candidiasis and Cryptoccus but each has its limitations in its method of administration and situs of activity. None of the available pharmaceutical preparations are both safe, effective, without side effects and can be administered orally and topically. The pharmaceutical preparations of the invention however, are safe, effective and cure candidiasis and Cryptoccus infection effectively without side effects.
Common side effects of the prior art compound Nystatin used for the treatment of oral thrush include nausea, diarrhea and hypersensitivity. Amphotericin B has many side effects, including renal toxicity, thrombophlebitis, hypokalemia, anemia, chills, fever, headache, nausea and anorexia. 5-Fluorocytosine produces skin rashes, diarrhea, nausea, hematopoietic and hepatic toxicities. The azole compounds including miconazole, ketoconazole, itraconazole and fluconazole all have the propensity of causing nausea, vomiting, headache, rash and sometime liver toxicity. These compounds when used to treat candidiasis and yeast infections of the vagina generally require prolonged treatment and in many cases result in recurrent yeast infections. Novak's Textbook of Gynecology, 10th Ed. (1980), p. 262-269. This is particularly the case with individuals having a weak immune system which require suppression therapy which require low dose treatments for long periods of time to control mycotic disease. Such suppression therapy is generally described for patients having weak immune systems or recurrent infection in such suppression therapy has been used in conjunction with ketoconazole, oral mystatin or low dose amphotericin B.
Gentian and gentian root have been in use for over 3,000 years as digestive stimulants and as ingredients in drinks and liquors. The Healing Herbs, (1991), p. 183-185; The Honest Herbal, 3rd Ed. (1993), p. 145. Traditional Chinese medicine has long used Radix gentianae Longdancao for a variety of liver, gallbladder and digestive treatments; Chinese Medicinal Herbs (1973), p. 81-82; Chinese Herbal Medicine, (1986) p. 104. A Compilation of Chinese Literature in the 1980's, p. 255-277 also discusses the use and some of the chemical constituents of the plant Radix gentianae Longdancao. None of these references describe or discuss a use for gentian as an antifungal or yeast treatment of Candida or Cryptoccus. The Chemical Constituents of Oriental Herbs, (1982), p. 105-106, 256, 644-645, 1131, 1175; CRC Handbook of Medicinal Herbs, (1986); Kudo-Chemical Abstracts, Vol. 114 (1991) abstract 114:254, 021K; Song Chemical Abstracts, Vol. 106 (1987) abstract 106:60602q; and Sadritdinoy-chemical Abstracts, Vol. 78 (1973) abstract 79634b discuss general medicinal properties of gentian for treatment of fevers, rheumatism, general disability and ulcers, malaria and herpes as well as the chemical constituents of the plant. These references do not teach or suggest a treatment for yeast or fungal infections caused by Candida and Cryptococcus.
Recently and after the present testing of gentian in vivo for the treatment of Candida and Cryptoccus a paper is Phytochemistry, Vol. 41, No. 1, pp. 111-116 (1996) entitled "Secoiridoids and Antifunaal Aromatic Acids From Gentiana Alaida" was published. This report substantiates in vitro activity against Candida albicans but does not teach or suggest antifungal or antiyeast activity against Cryptoccus or the treatment or activity against systemic candidiasis. This report furthermore does not teach or suggest the antifungal activity in weak or immuno-suppressed patients or the formulations of the invention that can be administered orally to treat Candida and Cryptoccus mycoses. It is further believed this recent paper is not prior art to the present invention which reduced the present invention to practice before the publication of this paper. This paper identified two chemical constituents with antifungal activity. They are methyl anofinic acid and methyl fomannoxin acid.
The prior art preparations in addition have not provided a safe, effective and nontoxic treatment of fungal and yeast infections or have cured the yeast infections within a few days to return the body to an immunological state necessary to ward off future fungal attacks. The prior art preparations have also not performed well in the treatment of patients with weak immune systems and have in some cases required injection and IV administration to treat candidiasis and cryptococcal fungal infections. The preparations of the invention unlike the prior art provide a safe, reliable and effective treatment of candidiasis and Cryptoccus in weak and compromised immune-deficient patients and may be administered topically or orally. The novel preparations and treatment of fungal infections caused by Candida and Cryptoccus include the application of gentian in the form of suppositories, capsules, creams, lotions, lozenges and liquid preparations.